Velkova, Simona Asenova; (2020) Moraxella catarrhalis and rhinovirus infection and co-infection of healthy and chronic obstructive pulmonary disease ciliated respiratory epithelium. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This research project investigated the effects of rhinovirus and Moraxella catarrhalis (M. catarrhalis) infection of the ciliated respiratory epithelium given the clinical infections caused by both pathogens in healthy individuals. However, as both rhinovirus and M. catarrhalis infection are known to exacerbate disease in a number of chronic respiratory diseases we were keen to determine if the underlying cellular response was different in such conditions. We chose to investigate chronic obstructive pulmonary disease (COPD) to allow comparison with results from healthy individuals. COPD is a progressive pulmonary disease characterised by chronic airway inflammation, emphysema, airway remodelling and chronic bronchitis. Exacerbations in COPD are primarily caused by bacterial and viral infections. As most studies looking at viral and bacterial infection of cells have focused on cell lines or basal cells we wanted to determine if differentiation to a ciliated phenotype, mimicking the host more closely affected response to infection. Primary healthy and COPD nasal tissue, differentiated at air-liquid interface allowed us to assess the initial interaction of M. catarrhalis and rhinovirus with the ciliated epithelium in vitro. Host-pathogen interactions were explored utilising high speed video, confocal and electron microscopy, western blotting, flow cytometry and immune-based assays. It was found that M. catarrhalis binds rapidly to the cilia of beating ciliated cells, altering ciliary function and invading epithelial cells, particularly COPD epithelial cells, initiating a cascade of signalling events involving the epidermal growth factor receptor and phosphoinositide-3 kinase pathway, leading to induction of pro-inflammatory cytokines. It was also demonstrated that rhinovirus targets ciliated cells in primary cultures, causing their shedding from the epithelial layer via apoptosis. This resulted in depletion of ciliated cells and a severely disrupted airway epithelium. Investigation of the mechanisms associated with bacterial-viral co-infections showed that rhinovirus pre-infection followed by a subsequent M. catarrhalis infection further decreased ciliary function of epithelial cultures and increased the release of pro-inflammatory mediators. Additionally, it was found that initial viral infection can potentially cause later dissemination of pathogens in the respiratory tract through triggered detachment of ciliated cells which appeared to have bound M. catarrhalis. Detached cells and reduction in ciliary function are likely to exacerbate airways obstruction.

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